The long-term objective of this proposed research is the formation of an in vitro cell culture model system for the study of cadmium-induced nephrotoxicity. The foundation of this model system is derived from the recently established cell culture of the human renal proximal tubule developed in this laboratory. In the last year, this culture system has been assessed with regard to the cellular responses which occur upon exposure to the heavy metal cadmium (Cd). Dose response curves demonstrated that these cells were very sensitive to low levels of Cd exposure and that these cells could become resistant to low levels of exposure and regain proliferative capacity. Both ultrastructural evaluation and electrophysiological analysis of these cells exposed to low Cd levels suggested an alteration in the structure and function of the cell membrane. Studies are proposed to examine: 1. alterations in proximal tubule cell transport and membrane structure that occur due to Cd exposure; 2. the localization of Cd within the cells when exposed both to CdC12 and the CdMT complex; 3. the metallothionein response of the cells when exposed to Cd; 4. if selective apical and basolateral membrane exposure to Cd alters the cellular toxicity of this compound; and, 5. whether or not similar alterations in proximal tubule cell membrane structure occur in in vivo models of Cd exposure. These studies should form a cell culture model system for the study of Cd-induced proximal tubule cell toxicity which compliments existing in vivo model systems.